ABSTRACT We have found that very few individuals survived to age 90+ free of dementia or disability, suggesting that almost the entire older population is at risk for incident dementia, especially Alzheimer's disease (AD). Further, it is now generally accepted that AD pathology starts decades prior to clinical onset, and the factors that alter the risk to express a clinical dementia are generally cumulative such that the presence of these factors in midlife are associated with dementia in old age. Therefore, it is imperative to understand the processes that lead to dementia at their very early stages, especially when both, vascular and AD pathology are emerging. This proposal will test the hypothesis that midlife systemic atherosclerotic and arteriosclerotic vascular disease, irrespective of subsequent treatment, is a major risk factor for the development of subclinical AD pathology, and its clinical expression. At the end of this study, we will know whether subclinical systemic vascular disease in midlife accelerates the presence of incident cerebral vascular disease and AD pathology in non-demented subjects, and whether the emerging vascular process leads to amyloid or tau protein deposition. In addition, we will be able to describe the compensatory mechanisms that allow a person to maintain normal cognition and function. If we can confirm our hypotheses, there will be strong evidence (esp., among middle aged individuals) for aggressive interventions to prevent the progression of vascular disease in order to ameliorate the development of subclinical AD pathology, and later the onset of its clinical symptoms. We will study non-demented individuals who are enrolled in an ongoing community-based Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study that began in 2003 and has collected a wealth of vascular measures over time. Approximately 1,400 participants are currently in the study; 43% are African- Americans. The subjects will be stratified in four groups based on the presence or absence of atherosclerosis (i.e., arterial endothelial dysfunction) or arteriosclerosis (i.e., pulse pressure) at study entry in 2003. Specifically, we will complete annual clinical evaluations (neuropsychological, neurological, psychiatric) on 500 non-demented subjects age 45-59 at the onset of HeartSCORE in 2003, and from this group, we will identify 400 who will undergo amyloid and tau ligand PET, structural and functional MRI scans, and cardiovascular evaluations (100 in each group); 45% of each group will be African-American. The PET, MRI, and cardiovascular exams will be repeated in a subgroup of 160 participants (40 in each group). Blood tests for cystatin C levels, lipid profile, and glucose levels will be obtained. Measures of physical activity and fitness will be obtained twice during the observation time. Using these data, we will address a series of linked hypotheses concerning the associations among subclinical vascular disease, changes in brain structure and perfusion, and subclinical AD pathology during the transition from middle age to old age.